Skin cancer is the most common form of cancer in the U.S., with more than 3.5 million skin cancers diagnosed annually (Rogers, H. W. et al., “Incidence of nonmelanoma skin cancer in the United States, 2006.” Arch. Dermatol. 2010; 146(3): 283-287). There are three (3) major types of skin cancer: (1) basal cell carcinoma; (2) squamous cell carcinoma; and (3) melanoma.
Basal cell carcinoma is the most common type of skin cancer in humans. These cancers tend to grow slowly and rarely spread to nearby lymph nodes or to distant parts of the body (www.cancer.org). Treatment methods include simple excision, radiation therapy and chemotherapy among others (www.cancer.org).
Squamous cell carcinoma grows and spreads more than basal cell cancers. This cancer is more likely to invade fatty tissues just beneath the skin and is more likely to spread to lymph nodes and/or distant parts of the body, although this is still uncommon (www.cancer.org). Treatment methods include excision, radiation therapy, systemic chemotherapy and lymph node dissection (www.cancer.org).
Malignant melanoma is a highly aggressive, chemo-resistant, less radio-responsive and lethal malignant neoplasm which is responsible for 60-80% mortality among all skin cancers, with a 5 year survival rate of 14%. J Clin Pathol. 2013 Mar. 23. [Epub ahead of print] Molecular biology of normal melanocytes and melanoma cells. Bandarchi B, Jabbari C A, Vedadi A, Navab R. Radiotherapy is included among the choice of treatments after the surgical treatment options to reduce the rate of recurrence, local control and limiting metastasis to bone or brain. Forschner A, Heinrich V, Pflugfelder A, Meier F, Garbe C, Clin Dermatol. 2013 May-June; 31(3):282-9. doi: 10.1016/j.clindermatol.2012.08.009. It accounts for only 4% of all skin cancer cases but causes more than 75% of all skin cancer deaths. Levine, Steven M., and Richard L. Shapiro. “Surgical Treatment of Malignant Melanoma: Practical Guidelines.” Dermatologic clinics 30.3 (2012): 487-501. In 2012, there were more than 75,000 diagnosed cases of melanoma, of which more than 9,000 cases were fatal. Siegel, R., Naishadham, D. and Jemal, A. (2012), Cancer statistics, 2012. CA: A Cancer Journal for Clinicians, 62: 10-29. Melanoma incidence and casualty rates have been consistently increasing in the United States ever since 1981. Currently, the national incidence rate of melanoma in Caucasian women younger than the age of 44 is increasing by 6.1% annually, reflecting the popular trend among young women of use of tanning booths and salons. Little, E. G., and M. J. Eide. “Update on the current state of melanoma incidence.” Dermatologic clinics 30.3 (2012): 355. Cancer registry data indicates that Caucasians have the highest age-adjusted rates of melanoma. Wu, Xiao-Cheng, et al. “Racial and ethnic variations in incidence and survival of cutaneous melanoma in the United States, 1999-2006.” Journal of the American Academy of Dermatology 65.5 (2011): S26-e1. It has been recently reported that tanning is a prevalent practice in America, with tanning rates in the teenage girl group approaching almost 40%. Balk, Sophie J., David E. Fisher, and Alan C. Geller. “Teens and Indoor Tanning: A Cancer Prevention Opportunity for Pediatricians.” Pediatrics 131.4 (2013): 772-785.
Melanoma is categorized into four central subtypes: Superficial Spreading Melanoma (SSM), Lentigo Maligna Melanoma (LMM), Acral Lentiginous Melanoma (ALM), and Nodular Melanoma (NM). SSMs are the most common type of melanoma in the Caucasian population, accounting for 70% of all diagnosed melanoma cases. Longo, Caterina, Alice Casari, and Giovanni Pellacani “Superficial spreading melanoma.” Reflectance Confocal Microscopy for Skin Diseases, Springer Berlin Heidelberg 2012. 151-178. Thin lesions are predominantly in a radial growth phase for months and years before reaching vertical growth. Garbe, Claus, et al. “Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline.” European Journal of Cancer 46.2 (2010): 270-283.
Among the genetic factors, BRAF V600E is the most common mutation associated with development of melanoma and is present in greater than 50% of all melanoma cases. Colombino M., et al., BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients with Melanoma. J Clin Oncol. 2012 Jul. 10; 30(20):2522-9. Epub 2012 May 21; McCubrey et al. Adv Enzyme Regul. 2006; 46:249-279. Armelle Calipel, Gaelle Lefevre, Celio Pouponnot, Frédéric Mouriaux, Alain Eychène and Frédéric Mascarelli. Mutation of B-Raf in Human Choroidal Melanoma Cells Mediates Cell Proliferation and Transformation through the MEK/ERK Pathway. J. Biological Chem. 2003. Functions of BRAF include regulation of cell growth, differentiation, and survival. Davies H., et al., Mutations of the BRAF gene in human cancer. Nature 2002. BRAF is a protein kinase and acts as the MAPKKK (W. Kolch, Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions, Biochem J. 2000) in the ERK pathway, an extracellular-signal-regulated kinase network. Eckerle Mize D., Bishop M., Resse E., Sluzevich J. In: Riegert-Johnson D L., Boardman L A., Hefferon T., Roberts M, editors. Familial Atypical Multiple Mole Melanoma Syndrome. Cancer Syndromes [Internet]. Bethesda (Md.): National Center for Biotechnology Information (US); 2009. The mutation at the v600E position causes the amino acid valine to become replaced with glutamic acid, a phosphomimetic, leading to hyperactive kinase activity. FAMMM (Family Atypical Multiple Mole Melanoma Syndrome) is a condition in which a person from a cutaneous melanoma family gets a large number of atypical nevi. Rafehi H., Orlowski C., Georgiadis G T., Ververis K., El-Osta A., Karagiannis “Clonogenic assay: adherent cells,” J. Vis Exp. 2011 Mar. 13; (49). pii: 2573. doi: 10.3791/2573. It has been acknowledged that several cases of melanoma within a family are connected to autosomal dominant inheritance. Host Risk Factors, Ultraviolet Index of Residence, and Incident Malignant Melanoma In Situ Among US Women and Men; Andrew C. Walls, Jiali Han, Tricia Li and Abrar A. Qureshi*, 2012. Other higher risk factors include appearance of multiple nevi on extremities, family history of melanoma, dysplastic nevi syndrome, severe and persistent sunburns and hair color. Balch C. M., Soong S. J., Gershenwald J. E., et al. Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19:3622-3634.
After melanoma has been diagnosed, there are five standard types of treatment used: surgery, chemotherapy, biologic therapy, targeted therapy, and radiation therapy. Surgical excisions are an early treatment method utilized for patients with thin, non-invasive lesions; excisional biopsies are conducted for easy histological evaluation and assessing excision margins of the remaining tumor. Stevens, Graham, and Angela Hong. “Radiation therapy in the management of cutaneous melanoma” Surgical Oncology Clinics of North America 15.2 (2006): 353-371.
Melanoma has a high potential for systemic metastasis. Incorporation of radiotherapy in management of melanoma is important since metastasis often occurs in the CNS of the patients with a failing response to systemic therapy in most cases. Stevens G, McKay M J, Lancet Oncol. 2006 July; 7(7):575-83. Dispelling the myths surrounding radiotherapy for treatment of cutaneous melanoma; Mohammad K Khan, Niloufer Khan, Alex Almasan, and Roger Macklis. Future of radiation therapy for malignant melanoma in an era of newer, more effective biological agents, OncoTargets Thera. 2011; 4: 137-148.
Generally, advancements in radiation therapy have led to delivery techniques incorporating a high degree of computer control. Shepard, David M., et al. “Optimizing the delivery of radiation therapy to cancer patients.” Siam Review 41.4 (1999): 721-744. Developments in imaging technology have allowed an advanced level of complexity to be integrated into radiotherapy treatment planning systems. Bucci, M. Kara, Alison Bevan, and Mack Roach “Advances in radiation therapy: conventional to 3D, to IMRT, to 4D, and beyond” CA: a cancer journal for clinicians 55.2 (2005): 117-134. Radiation therapy, including intensity modulated radiation therapy, enables clinical application of highly conformal dose distributions. Ezzell, Gary A., et al. “Guidance document on delivery, treatment planning, and clinical implementation of IMRT: Report of the IMRT subcommittee of the AAPM radiation therapy committee.” Medical physics 30 (2003): 2089. Each radiation therapy field contains small, irregular, off-axis fields, resulting in delivery of isodose distributions more conformal than conventional treatment plans. Palta, Jatinder R., Chihray Liu, and Jonathan G. Li. “Quality assurance of intensity-modulated radiation therapy.” International Journal of Radiation Oncology* Biology* Physics 71.1 (2008): S108-S112. The intensity of each distributed beamlet is adjusted according to the necessary planning dose objectives. The intensity patterns are then decomposed into multi leaf collimator (MLC) shapes for sequencing. Broderick, Maria, Michelle Leech, and Mary Coffey “Direct aperture optimization as a means of reducing the complexity of Intensity Modulated Radiation Therapy plans” Radiat Oncol 4.8 (2009): 1-7. Radiotherapy has become increasingly used over the years and is now rapidly being implemented in clinical departments throughout the United States. Purdy, James A “From new frontiers to new standards of practice: advances in radiotherapy planning and delivery” (2007): 18-39.
Past radiation treatments on cancer patients have shown effective coverage of target tumor tissue while reducing exposure to volumes of surrounding normal tissue, even at high dose levels. Zelefsky, Michael J., et al. “Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer” Radiotherapy and Oncology 55.3 (2000): 241-249. Multiple static multileaf collimator segments used in combination with radiation therapy have proven to be an efficient method for attaining uniform dose in cancer treatment. Kestin, Larry L., et al. “Intensity modulation to improve dose uniformity with tangential breast radiotherapy: initial clinical experience” International Journal of Radiation Oncology* Biology* Physics 48.5 (2000): 1559-1568.
Over the years, machines based on kilovoltage x-rays and gamma rays have been replaced by linear particle accelerators (LINACs) that produce up to 18 MV of energy for conformal therapy Xu, X. George, Bryan Bednarz, and Harald Paganetti “A review of dosimetry studies on external-beam radiation treatment with respect to second cancer induction.” Phys. Med. Biol 53 (2008): R193-R241. Publications involving radiation treatments and radiation therapy report usage of LINACs set at a common 400 cGy/min dose rate. Wolff, Dirk, et al. “Volumetric modulated arc therapy (VMAT) vs. serial tomotherapy, step-and-shoot IMRT and 3D-conformal RT for treatment of prostate cancer.” Radiotherapy and Oncology 93.2 (2009): 226-233. Adams, Elizabeth J., et al. “Clinical implementation of dynamic and step-and-shoot IMRT to treat prostate cancer with high risk of pelvic lymph node involvement” Radiotherapy and oncology 70.1 (2004): 1-10. Gierga, David P., et al. “Quantification of respiration-induced abdominal tumor motion and its impact on IMRT dose distributions” International Journal of Radiation Oncology* Biology* Physics 58.5 (2004): 1584-1595. The Varian TrueBeam radiotherapy system, by Varian Medical Systems of Palo Alto, Calif., has been tested and shown to be feasible for delivering radiation therapy to various tumor sites using flattening filter free (FFF) beams. Scorsetti, Marta, et al. “Feasibility and early clinical assessment of flattening filter free (FFF) based stereotactic body radiotherapy (SBRT) treatments” Lung34 (2011): 48. The TrueBeam system has been tested to show consistent dose accuracy efficiency even as dose rate increases. Dose accuracy has been tested to be maintained even at dose rates as high as 2,400 cGy/min. Li, Ji, et al. “Improvements in dose accuracy delivered with static-MLC IMRT on an integrated linear accelerator control system” Medical Physics 39 (2012): 2456.
Integration of radiation therapy into the management plan of melanoma can enable improvement of loco-regional control and alleviation of symptoms from metastatic disease. Modern day linear accelerators with flattening filter free mode may be used to increase dose rate capabilities producing advantages over conventional radiotherapy such as the capability for increasing the delivery of radiation at rates per minute not previously available. In addition, the image guidance, along with volumetric arc therapy capabilities, exhibit improved target conformity, sparing normal tissue surrounding the lesion and dose escalation in the target volume. Its ability to deliver the doses in concave isodose profiles to minimize the injury to the normal surrounding tissue is considered as a significant improvement in the area of radiation oncology. Calabro A., Singletary S. E., Balch C. M., Patterns of relapse in 1001 consecutive patients with melanoma nodal metastases. Arch Surg. 1989; 124:1051-1055. Byers R. M., The role of modified neck dissection in the treatment of cutaneous melanoma of the head and neck, Arch Surg 1986; 121:1338-1341. Kirkwood J. M., Ibrahim J. G., Sosman J. A., et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma. Results of intergroup trial E1694/S9512/C509801. J. Clin Oncol. 2001; 19:2370-2380. Florian Sterzing et al: Radiobiological investigations of dose rate effects on IMRT.
The emergence of Intensity Modulated Radiation Therapy (IMRT), using advanced software to plan a precise dose of radiation, based on tumor size, shape and location is helpful in treatment of melanoma. A computer-controlled linear accelerator may be used to deliver radiation in sculpted doses that match the exact 3D geometrical shape of the tumor, including concave and complex shapes. Local dose elevation with radiation therapy has led to good local and distant tumor control as well as minimization of toxicity due to radiation exposure for past melanoma patients. Combs, Stephanie E., et al. “Local high-dose radiotherapy and sparing of normal tissue using intensity-modulated radiotherapy (IMRT) for mucosal melanoma of the nasal cavity and paranasal sinuses” Strahlentherapie und Onkologie 183.2 (2007): 63-68. Hypofractionated radiation used as an adjuvant therapy method for melanoma treatment has been proven to enable a high rate of in-field control and low risk of toxicity. Hallemeier, C. L., et al. “Adjuvant Hypofractionated Intensity Modulated Radiation Therapy (IMRT) After Resection of Regional Lymph Node (LN) Metastases in Patients With Malignant Melanoma of the Head and Neck” International Journal of Radiation Oncology* Biology* Physics 84.3 (2012): S505-S506.
A series of close to diploid human melanoma cell lines were shown to be highly resistant to UV radiation. Chalmers, A H et al, “Resistance of Human Melanoma Cells to Ultraviolet Radiation,” Cancer Res. 1976; 36: 1930-1934. It was suggested that such resistance could confer a proliferative advantage to the tumor cells under conditions of irradiation. Id.
The described invention provides a method to treat cancer by radiation therapy in which a high dose rate is used to deliver ionizing radiation at a low dose in the 25-50 centrigray (cG) range, i.e., 6-10 times lower than a standard irradiation dose, which is effective to kill cancer cells 4-5 times more effectively than a standard dose of ionizing radiation.